Biologically active compounds

ABSTRACT

WHEREIN R1, R2, R3 and R4 have designated meanings, obtained by nitration of a parent un-nitrated compound and wherein ring A is saturated or has 1 or 2 double bonds.   Anti-allergic compounds, their production, and pharmaceutical compositions and their administration for the inhibition of diseases associated with allergic and immunological reactions are described. The compounds are nitro-indane-diones of the formula:

United States Patent 1191 Buckle et al.

[451 Nov. 18, 1975 BIOLOGICALLY ACTIVE COMPOUNDS [75] Inventors: Derek Richard Buckle, Redhill;

Harry Smith, Horsham, both of England [73] Assignee: Beecham Group Limited, England [22] Filed: Oct. 24, 1973 21 Appl. No.: 409,164

[30] Foreign Application Priority Data Nov. 11, 1972 United Kingdom 52203/72 [52] US. Cl. 260/468 G; 424/263; 424/305; 424/331; 260/297 B; 260/297 T; 260/488 B; 260/586 R [51] Int. Cl. C07C 69/02; C07C 69/12 [58] Field of Search 260/586 R, 297, 514 G,

Severina et al., lzv. Akad, Nauk SSSR, Ser. Khim, Vol.5 pp. 1111 to 1115 (1967).

Primary Examiner-John D. Randolph [57] ABSTRACT Anti-allergic compounds, their production, and phar maceutical compositions and their administration for the inhibition of diseases associated with allergic and immunological reactions are described. The compounds are nitro-indane-diones of the formula:

R R 1 o wherein R R R and K, have designated meanings, obtained by nitration of a parent un-nitrated compound and wherein ring A is saturated or has 1 or 2 double bonds.

' 7 Claims, No Drawings BIOLOGICALLY ACTIVE COMPOUNDS This invention relates to pharmaceutical compositions which are useful in the inhibition of the effects of certain types of antigen-antibody reactions, and are therefore of value in the prophylaxis and treatment of diseases associated allergic or immunologicalv reactions, e.g., certain types of asthma and hay-fever and also in the treatment of rhinitis. The invention also includes novel compounds having such anti-allergic activity and a method for their preparation.

According to the present invention, there is provided a compound of formula (I) or a salt thereof:

wherein R R R and R are each hydrogen or alkyl, aryl, alkoxy, aralkyl, acyloxy, heterocyclic, carboxy, alkoxycarbonyl or halogen groups, or any two of the groups R R R and R may be joined in a carbocyclic or heterocyclic ring system, and wherein the ring marked A is fully saturated or contains 1 or 2 double bonds. 4

Examples of groups R R R and R which may be present in the compounds of this invention include methyl, ethyl, n-and iso-propyl, n-, sec-, and tert-butyl: methoxy, ethoxy, n-and iso-propoxy n-, sec-, and tertbutoxy, phenyl, benzyl, acetoxy, propionoxy n-and isobutyroxy pyridyl methoxycarbonyl, ethoxycarbonyl n-and sio-propoxycarbonyl fluoro, chloro, bromo, or iodo groups. In addition any two of the groups R R R and R taken together may represent the residue of a l 2-phenylene or 1 2-cyclohexylene ring, which may carry one or more of the substituents listed above.

The compounds of this invention may be prepared by a process which comprises nitrating the parent compound of formula (II):

wherein R R R R and ring A are as defined with respect to formula (I). The nitration step may be carried out at various temperatures, although usually below 25C. In general a temperature of from 30C to +20C will be suitable with 20C being suitable on most occasions. Preferably the nitration step is carried out using fuming nitric acid, but other nitrating agents such as the nitrous fumes generated with concentrated nitric acid and arsenic oxide acetic acid and concentrated nitric acid or concentrated nitric acid itself may be used. Y

The salts of compounds (I) are preferably pharmaceutically acceptable salts, e.g. alkali metal salts such as sodium or potassium and salts with organic bases such as amines or amino compounds. Compounds (I) and their salts may exist on occasions as an anhydrous form or as various hydrates.

The invention also includes a pharmaceutical composition comprising a compound of formula (1) above or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers.

The compositions of this invention may be presented as a microfine powder for insufflation, e.g., as a snuff or in capsules of hard gelatine. They may also be presented together with a sterile liquid carrier for injection. Some of the compounds (I) appear to be active when given orally and thus the compositions of this invention may be in the form of tablets, capsules, pills or syrups. Preferably the compositions are presented in unit dosage or in a form in which the patient can administer to himself a single dosage unit. If desired, a small amount of a bronchodilator compound may be incorporated in the compositions of the invention, both to inhibit the cough response and to provide immediate relief during an asthmatic attack.

The following Examples illustrate the preparation and properties of some of the compounds of this invention:

EXAMPLE 1 a. 5,6-Dimethyl cis-3a, 4,7,7a-tetrahydroindanel ,3-dione A solution of 4-cyclopentene-l,3-dione (548g; 0.06 mole) and 2,3-dimethyl butadiene (10.4g; 0.127 mole) in dry benzene (20ml) were treated with a few crystals of 2,5-di-t-butyl hydroquinone and allowed to stand at ambient temperature for 4 days. After refluxing for l5 mins the mixture was cooled and the pale orange solid filtered. Recrystallisation from benzene methanol afforded the title produce as a white solid, mp. l57158C (Found: C, 74.17; H, 7.89; C H O requires: C, 74.l3: H, 7.92%).

b. 5,6-Dimethyl-2-nitro cis-3a,4,7,7a-tetrahydroindane- 1 ,3-dione Fuming nitric acid (1.0 ml) was added dropwise to a suspension of 5,6-dimethyl cis-3a,4,7,7a-tetrahydroindane-l,3-dione (0.89g; 0.05 mole) in dry ether (8ml) at 20C and the mixture maintained at this temperature for 45 mins after the addition. On warming to 5C a further 05ml of fuming nitric acid was added and the mixture stirred for lhr. at room temperature. Filtration afforded the 2-nitro derivative as a yellowish solid mp. (methanol) 156l57.5C (Found: C, 59.19; H, 5.98; N, 6.05; C H NQ, requires: C, 59.19; H, 5.87; N, 6.27%).

EXAMPLE 2 a. 5,6-Dimethyl cis-hexahydroindane-l, 3-dione A solution of 5,6-dimethyl cis -3'a,4,7,7a-tetrahydroindane -l,3-dione (1.78g; 0.01 mole) in methanol (l5ml.) was added to pre-reduced 10% palladinised charcoal (0.15g) in methanol (l5ml.) and the mixture hydrogenated till one equivalent of hydrogen was absorbed. Filtration and evaporation then gave the hexahydroindane dione as a white crystalline solid, mp. (ethyl acetate, ether) l357C (Found: C, 73.03; H, 8.97; C H O requires: C, 73.30; H, 8.95%).

b. 5,6-Dimethyl cis-hexahydro-Z-nitro indane- 1 ,3-dione Nitration of 5,6-dimethyl cis-hexahydroindane-l,3- dione as described in example lb afforded the title product as a white crystalline solid, mp. (methanol) l69170C. (Found: C, 58.35; H, 6.77; N, 6.39; C H, NO requires: C, 58.66; H, 6.71; N, 6.22%). 1

EXAMPLE 3 a. 4,7-Dimethyl cis-3a,4,7,7a-tetrahydroindane-1 ,3-dione This was prepared as for example 1(a) using hexa- 2,4-dione in place of 2,3-dimethyl butadiene, m.p. (methanol) 210C. (Found: C, 74.13; H, 7.99; C H O requires: C, 74.13; H, 7.92%).

b. 4,7-Dimethyl-2-nitro cis-3a,4,7,7a-tetrahydroindane- 1 ,3-dione Nitration of 4,7-dimethyl cis-3a,4,7,7a-tetrahydroindane-l,3-dione according to the procedure of example 1 (b) afforded the 2-nitro derivative; m.p. (methanol) l278C. (Found: C, 58.85; H, 5.99; N, 6.31; C H NO, requires: C, 59.19; H, 5.87; N, 6.27%).

EXAMPLE 4 a. 4,7-Dimethyl cis hexahydroindane-l,3-dione A solution of 4,7-dimethyl cis-3a,4,7,7a-tetrahydroindane-1,3-dione in methanol was reduced over palladinised charcoal to give the title compound as a white crystalline solid, mp. (methanol) 194C. (Found: C, 73.28; H, 9.10; C H -O requires: C, 73.30; H, 8.95%).

b. 4,7-Dimethyl cis-hexahydro-Z-nitro indane- 1,3-dione Nitration of 4,7-dimethyl cis hexahydroindane-l,3- dione as for the 5,6-dimethyl analogue (example 1(a) gave the 2-nitro derivative; m.p. (ethanol) 1 1 1-1 12C. (Found: C, 58.45; H, 6.80; N, 6.01; C H NO requires: C, 58.66; H, 6.71; N, 6.22%).

EXAMPLE 5 a. 4-Carboxy cis-3a,4,7,7a-tetrahydroindane-l ,3-dione A solution of 4-cyclopentene-1,3-dione (9.6g; 0.1 mole) in dry benzene (30ml.) was added to l-carboxy butadiene (9.8g; 0.1 mole) and a few crystals of 2,5-dit-butyl hydroquinone added. The orange solution was stood at room temperature for 3 days and evaporated to small bulk to induce crystallisation. Filtration followed by trituration with anhydrous ether gave the desired product, mp 182C. (H. 0. House and G. H. Rasmunsen, J. Org. Chem., 1963, 28 27 quote mp. 191C).

b. 4-Carboxy-2-nitro cis-3a,4,7,7a-tetrahydroindanel 3-dione To a stirred suspension of 4-carboxy cis-3a,4,7,7atetrahydroindane-1,3-dione (0.585g; 0.003 mole) in dry ether (5 ml.) at 5C was added fuming nitric acid (1.0ml.) dropwise. After stirring 1 hr. at 5C the mixture was kept for 2 hr. at room temperature, filtered and washed well with dry ether to afford analytically pure title compound, mp. 175C (decomp.). (Found: C, 50.09; 'H, 3.88; N, 5.71; C H NO requires: C, 50.22; H, 3.79; N, 5.86%).

EXAMPLE 6 a. Tricyclo [5,2,1,0 dec-8-ene-3,5-dione b. 4-Nitro tricyclo [5,2,1,0 dec-8-ene-3,5-dione Nitration of tricyclo [5,21,0 1 dec-8-ene-3,5-dione according to example lb, afforded the 4-nitro derivative, m.p. (methanol) 195C (decomp.). (Found: C, 58.17; H, 4.49; N, 6.48; C H NO requires: C, 57.97; H, 4.38; N, 6.76%).

EXAMPLE 7 a. Tricyclo [5,2,1,0 decane-3,5-dione Reduction of tricyclo [5,2,1,0 dec-8-ene-3,5- dione over 10% palladinised charcoal as described in example 2a gave the dihydro product, m.p. (methanol) 177C. (Found: C, 73.15; H, 7.51; C H O requires: C, 73.15; H, 7.37%).

b. 4-Nitro tricyclo [5,2,l,0 decane-3,5-dione To a stirred suspension of tricyclo [5,2,1,0 decane-3,5-dione (0.82g; 0.05 mole) in dry ether (8ml.) was added fuming nitric acid (lml) at 20C. After stirring for 1 hr. at -20C the solid was filtered, washed with cold, dry ether and recrystallised from methanol, mp 167C. (Found: C, 57.69; H, 5.49; N, 6.46; C H NO requires: C, 57.41; H, 5.30; N, 6.70%).

EXAMPLE 8 a. 4-Methyl-cis-3a,4,7, 7a-tetrahydroindane- 1 ,3-dione A solution of 4-cyclopentene-1,3-dione (5.84g; 0.06 mole) in dry benzene (20ml.) was stood for 4 days with 1,3-pentadiene (8.9g; 0.122 mole) and a little 2,5-di-tbutyl hydroquinone (10mg) and the crystalline solid filtered off and recrystallised from methanol to yield the title dione, m.p. l3940C. (Found: C, 72.96; H, 7.51; C H O requires: C, 73.15; H, 7.34%).

b. 4-Methyl-2-nitro-cis-3 a,4,7,7a-tetrahydroindanel ,3-

dione Nitration of 4-methyl-cis-3a,4,7,7a-tetrahydroindane-1,3-dione as described in example 7b afforded the 2-nitro derivative, m.p. (methanol) 101C. (Found: C, 57.13; H, 5.30; N, 6.47; C H NO requires: C, 57.41; H, 5.30; N, 6.70%).

EXAMPLE 9 a. 4-Carbomethoxy-cis-3 a,4,6,7a-tetrahydroindane-1 ,3-

dione The reaction of methyl penta-2,4-dienoate with cyc1opentene-1,3-dione according to example 1a, gave the title Diels-Alder adduct, m.p. (methanol) 196C. (Found: C, 63.52; H, 5.77; C H O requires: C,'63.45; H, 5.81%).

b. 4-Carbomethoxy-2-nitro-cis-3a,4,7,7a-tetrahyclroindane- 1 ,3-dione Treatment of 4-carbomethoxy-cis-3a,4,7,7a-tetrahydroindane-1,3-dione with fuming nitric acid at -20C yielded the 2-nitro derivative, m.p. (methanol) 139C. (Found: C, 52.14; H, 4.32; N, 5.46; C H NO requires; C, 52.18; H, 4.38; N, 5.53%).

EXAMPLE a. 4-Acetoxy-cis-hexahydroindane- 1 ,3-dione Catalytic reduction of 4-acetoxy-cis-3a,4,7,7a-tetrahydroindane-l,3-dione (mp. 168C) according to example 2a afforded the hexahydro derivative, m.p. (methanol) 135-138C. (Found: C, 62.92; H, 6.89; C H Q, requires: C, 62.85; H, 6.71%).

b. 4-Acetoxy-cis-hexahydro-2-nitro-indanel ,3-dione Nitration of 4-acetoxy-cis-hexahydroindane-l,3- dione at C gave the title compound, m.p. (methanol) 147C. (Found: C, 51.59; H, 5.22; N, 5.49; C H NO requires: C, 51.76; H; 5.13; N, 5.49%).

EXAMPLE 1 1 a. 4-Methyl-cis-hexahydroindane-l ,3-dione Reduction of 4-methyl cis-3a,4,7,7a-tetrahydroindane-l,3-dione over 10% palladinised charcoal as described in example 2a afforded the dihydro product, m.p. (MeOH) 122C. (Found: C, 72.48; H, 8.48; C H O requires: C, 72.26; H, 8.49%).

b. 4-Methyl-2-nitro-cis-hexahydroindane-1 ,3-dione Nitration of a stirred suspension of 4-methyl cis-hexahydroindane-l,3-dione as described in example lb gave the 2-nitro derivative, m.p. (MeOH) 1 18120C. (Found: C, 56.41; H, 6.12; N, 6.69; C H NO requires: C, 56.86; H, 6.20; N, 6.63%).

EXAMPLE 12 a. Tricyclo 5,2,2,O undec-8-ene-3,5-dione b. 4-Nitro tricyclo [5,2,2,0 undec-8-ene-3,5-dione Tricyclo [5,2,2,0 undec-8-ene-3,5-dione nitrated at 20C as described gave the 4-nitro derivative, m.p. (MeOH) 206C. (Found: C, 59.63; H, 5.11; N, 6.03; C H NO requires: C, 59.73; H, 5.01; N, 6.33%).

EXAMPLE 13 a. Tricyclo [522,0 undecane-3,5-dione Reduction of tricyclo [522,0 undec-8-ene-3,5- dione over 10% palladinised charcoal as described in example 2a gave the title compound; m.p. (MeOH) 2545C. (Found: C, 73.94; H, 7.90; C H O requires: C, 74.13; H, 7.92%).

b. 4-Nitro tricyclo [5,2,2,0 undecane-3,5-dione EXAMPLE 14 7 Biological Results All of the 2-nitro indane-1,3-diones prepared in the preceeding Examples were submitted for biological testing. The test system was the Rat Passive Cutaneous Anaphylaxis (PCA) test described below in (I1).

1. Serum containing heat labile homocytotropic antibody was raised in rats by a method similar to that used by Mota (I. Mota Immunology 1964, 7, 681).

Male Wistar rats of 250-300g. were injected intraperitoneally with 0.5m] of Bordetella pertussis vaccine (containing 4 X 10 dead oranism per ml) and subcutaneously with 0.5ml of an emulsion of 100mg. of ovalbumin in 2ml of saline and 3ml of incomplete Freunds adjuvant. Rats were bled by cardiac puncture on day 18, the blood was pooled and separated and serum stored at 20 and thawed only once before use.

11. The P.C.A. test was similar to that described by Ovary and Bier (A. Ovary and O. E. Bier, Proc. Soc.

Exp. Biol. Med. 1952, 81, 584) and Goose and Blair (J. Goose and A.M.J. N Blair, Immunology 1969, 16, 749).

0.1ml of each of six twofold serial dilutions of the serum in 0.9% saline were injected intradermally into separate sites on the shaved dorsal surface of 250-350g. Wistar rats. 72 hours later the animals were challenged by i.v. injection of 0.3ml of 1% ovalbumin mixed with 0.1ml of a 5% solution of pontamine sky blue dye both in isotonic saline buffered with pH 7.2 Sorenson buffer (P.B.S.). The rats were killed after 20 minutes and the diameter of the blue wheals at the antibody injection sites were measured.

The starting dilution of the serum was adjusted so that there was no response, after challenge, at the site of injection of the highest dilution and a maximum response at the lowest dilution. Typically six twofold serial dilutions of the serum from l/4 to H128 were used.

Compounds were tested for their ability to reduce the diameter of the wheals at the injection sites of dilutions of antibody which on all the controls have less than maximum response. Amounts of the compounds were administered to rats each amount to a test group of six animals at a specified time prior to intravenous challenge with ovalbumin. The diameters of the blue wheals which developed on the test group of animals were compared with those on a control group of six animals treated in the same way as the test group, but which had not received the compound under test.

% Inhibition of P.C.A. (l

Test compound Dose Time 7clnhibition of Product of example No mg/kg (Mins) PCA response l(b) 25. 16 I00 0 61 25 30 6 100 30 42 2(b) 25 0 7 l0() 0 31 I00 0 8 25 30 7 100 30 -l 4(b) 25 0 4 25 60 l3 7 I00 60 l l 5(b) 0 2 I00 0 -3 25 l 100 30 '6 (Kb) 25 O -9 v 100 O 4 25 60 9 100 60 17 7(b) 2S 0 8 -continued Test compound Dose Time 7rlnhibition of Product of example No mg/kg (Mins) PCA response lOO O 41 25 30 13 30 52 9(b) 25 0 2 100 O 10 25 30 9 A 100 30 -5 l0(b) 25 0 12 I00 0 l l 25 3O 17 lOO 30 20 ll(b) 25 0 l3 lOO O l l 25 3O 8 I00 30 I7 12(b) 25 O O I00 0 -3 25 30 29 100 30 32 13(b) 25 0 14 100 O 8 25 30 13 100 30 29 indanel ,3-dione 

1. THE COMPOUND 5,6-DIMETHYL-2-MITRO CIS-3A,4,7,7A-TETRAHYDROINDANE-1,3-DIONE.
 2. The compound 5,6-dimethyl cis-hexahydro-2-nitro indane-1,3-dione.
 3. The compound 4,7-dimethyl 2-nitro cis-3a,4,7,7a-tetrahydroindane-1,3-dione.
 4. The compound 4,7-dimethyl cis-hexahydro-2-nitro indane-1,3-dione.
 5. The compound 4-carboxy-2-nitro cis-3a,4,7,7a-tetrahydroindane-1,3-dione.
 6. The compound 4-carbomethoxy-2-nitro-cis-3a,4,7,7a-tetrahydroindane-1,3-dione.
 7. The compound 4-acetoxycis-hexahydro-2-nitro-indane-1,3-dione. 